ORIGINAL
RESEARCH
K. Johkura
Y. Nakae
Y. Kudo
T.N. Yoshida
Y. Kuroiwa
Early Diffusion MR Imaging Findings and
Short-Term Outcome in Comatose Patients with
Hypoglycemia
BACKGROUND AND PURPOSE: The relationship between the MR imaging features and clinical outcomes in patients with hypoglycemic encephalopathy has always been evaluated retrospectively. The
aim of this study was to prospectively evaluate whether MR imaging features of patients presenting
with hypoglycemic coma are predictive of short-term (1-week) outcomes.
MATERIALS AND METHODS: Subjects were 36 consecutive patients with hypoglycemia who were in a
comatose state on arrival at our hospital from April 2006 to March 2010. MR imaging findings on arrival
in relation to the patients’ clinical course after glucose infusion were evaluated.
RESULTS: Thirteen of the 36 patients showed no MR imaging abnormalities on arrival. DWI revealed focal
lesions involving the internal capsule in 13 patients and lesions involving bilateral hemispheric white matter
in 10 patients. After glucose administration, the patients without lesions and patients with focal internal
capsule lesions recovered completely within 1 day. However, patients with diffuse white matter lesions did
not recover even within 1 week despite glucose administration. There was no statistical difference in the
initial blood glucose levels among patients with the various types of MR imaging findings.
CONCLUSIONS: On early MR imaging, hypoglycemic brain injury may first appear in the internal
capsule and then spread into the hemispheric white matter. The absence of a lesion or the presence
of a focal internal capsule lesion may suggest a good outcome. However, diffuse hemispheric white
matter lesions may indicate a poor 1-week outcome.
A
sudden decrease in the serum glucose level may cause
coma. Most hypoglycemic comatose patients regain consciousness after glucose infusion. However, hypoglycemia can
cause irreversible brain damage that reduces the patient to a
persistent vegetative state or death.
With widespread use of high-field MR imaging scanners,
various MR imaging findings have been reported in patients
with hypoglycemia. DWI in various cases has led to the identification and description of hyperintensity lesions in the cerebral cortex,1-4 basal ganglia,1,2,5 subcortical white matter,3,6,7
posterior limb of the internal capsule,4,6,8-10 and splenium of
the corpus callosum.4,7,8,10 A series of 11 patients with hypoglycemic encephalopathy in whom lesions were identified by
MR imaging has been reported recently.11 The reports have all
been based on retrospective evaluation of the MR imaging
findings.
We conducted a prospective study in which we evaluated
MR imaging findings with respect to early prognosis after glucose infusion in a consecutive series of patients hospitalized
with hypoglycemic coma. The aims of the study were to document the evolution of hypoglycemic brain injury neuroradiologically and to determine the early MR imaging features of
hypoglycemic brain injury that indicated reversible functional
brain damage and those that indicated irreversible brain
damage.
Received July 4, 2011; accepted after revision September 5.
From the Department of Neurology and Stroke Center (K.J., Y.N.), Hiratsuka Kyosai
Hospital, Hiratsuka, Japan; and Department of Neurology (Y. Kudo, T.N.Y., Y. Kuroiwa),
Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Please address correspondence to Ken Johkura, MD, PhD, Department of Neurology and
Stroke Center, Hiratsuka Kyosai Hospital, 9 –11 Oiwake, Hiratsuka 254-8502, Japan; e-mail:
[email protected]
http://dx.doi.org/10.3174/ajnr.A2903
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Materials and Methods
Design
The study was designed as a prospective observational study to be
conducted at a single institution. The study was approved by the institutional ethics committee. Oral informed consent was obtained
from patients’ family members.
Patients
Subjects were identified from among 114 patients with hypoglycemia
who visited our emergency department between April 2006 and
March 2010. The patients who were included in the study were transferred to our hospital in a comatose state on arrival and diagnosed
with hypoglycemia by blood laboratory tests. In this study, patients
with borderline blood glucose levels (40 – 69 mg/dL) were included
when they had a history strongly suggestive of hypoglycemia such as
insulin overdose. We excluded patients with another underlying condition that could contribute to their mental state, such as hypoxia,
hypotension, or hypothermia detected by a vital-signs monitoring
system in the emergency department; acidosis, infection, or intoxication detected by blood laboratory tests; or epilepsy suspected by focal
or generalized seizure. Thus, the final study group comprised 36 patients. When hypoglycemia was diagnosed, patients were treated immediately with 40 mL of 50% glucose, administered intravenously.
Thereafter, patients’ blood glucose levels were maintained at 150 –200
mg/dL. Blood glucose levels and MR imaging findings on arrival and
changes in the neurologic and MR imaging findings during the first
week after admission were evaluated; after the first 1-week period,
some patients were discharged from our hospital or transferred to
another hospital for rehabilitation.
MR Imaging
Each comatose patient underwent brain MR imaging, including DWI
on arrival just after blood sampling as long as the patient had no
BRAIN
contraindication for MR imaging such as an implanted cardiac pacemaker. Follow-up MR imaging was performed on the following day
(day 2) if a DWI abnormality (lesion) was found on arrival. If the DWI
abnormality had not disappeared by day 2, additional MR imaging
was performed 1 week after admission. All MR imaging studies were
performed with a 1.5T Symphony MR imaging scanner (Siemens,
Erlangen, Germany). Imaging sequences of the brain included spinecho T1-weighted, T2-weighted, FLAIR, and DWI sequences. From
DWI, ADC maps were constructed. The MR imaging parameters
were as follows: for T1-weighted imaging: TR/TE ⫽ 525–570/12–14
ms, matrix ⫽ 256 ⫻ 230; for T2-weighted imaging: TR/TE ⫽ 3550 –
4000/107–113 ms, matrix ⫽ 269 ⫻ 448; for FLAIR imaging: TR/TE/
TI ⫽ 8580 –9000/77–107/2200 –2300 ms, matrix ⫽ 272 ⫻ 320; and
for DWI: TR/TE ⫽ 3200/95 ms, matrix ⫽ 128 ⫻ 102, b ⫽ 1200
s/mm2. For all imaging sequences, the section thickness was 5 mm
and the FOV was 22 ⫻ 22 cm.
Analysis
Clinical and MR imaging evaluations of each patient were done by
one of the authors (K.J., Y.N., or Y. Kudo) who examined the patient
in the emergency department. Signal intensities of lesions were visually assessed on all MR imaging sequences. Results of the first MR
imaging evaluations were confirmed by another author who was
blinded to clinical data (T.N.Y. or Y. Kuroiwa).
After the initial DWI study (on admission), patients were divided
into groups according to the initial findings. ANOVA was used to
examine between-group differences in patient age and blood glucose
levels on arrival. JMP, Version 7 (SAS Institute, Cary, North Carolina)
was used for all statistical analyses. P ⬍ .05 was considered statistically
significant.
Results
There appeared to be no significant differences in the patients’
consciousness levels. All 36 patients were incapable of sensing
or responding to verbal and painful stimuli on arrival; there
were no patients who lost brain stem reflexes such as the pupillary reflex or who developed decorticate or decerebrate postural changes.
DWI on arrival showed areas of abnormal hyperintensity in 23 of the 36 patients. In 13 of these 23 patients,
hyperintensity lesions corresponding to hypointense signals on an ADC map were seen in the posterior limb of the
internal capsule; the internal capsule lesions were bilateral
in 7 patients, left-sided in 4, and right-sided in 2
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ORIGINAL RESEARCH
Fig 1. Two different DWI lesion patterns in patients with hypoglycemic coma are indicative of 2 different outcomes. When focal lesions involving the posterior limb of the internal capsule
(eg, patient 4, unilateral lesion, A; patient 9, bilateral lesions, B) were seen, outcomes were good. C and D, However when diffuse lesions involving bilateral hemispheric white matter
including the internal capsule, corona radiata, and centrum semiovale (eg, patient 19), were seen, outcomes were poor.
Table 1: Clinical characteristics of comatose patients with hypoglycemia with focal DWI lesions
No./Age
(yr)/Sex
1/63/M
Blood Glucose
Level (mg/dL)
12
2/76/F
3/83/F
24
32
4/66/M
5/56/F
6/73/M
7/80/M
8/90/F
9/67/M
10/91/F
11/83/F
12/81/M
13/81/F
30
32
18
16
29
42
22
47
42
41
DWI Pattern on Arrival
Left internal capsule, both
cerebral peduncles
Bilateral internal capsule
Right internal capsule, splenium
of the corpus callosum
Left internal capsule
Left internal capsule
Bilateral internal capsule
Bilateral internal capsule
Left internal capsule
Bilateral internal capsule
Right internal capsule
Bilateral internal capsule
Bilateral internal capsule
Bilateral internal capsule
DWI Pattern
on Day 2
No abnormality
No abnormality
No abnormality
No
No
No
No
No
No
No
No
No
No
abnormality
abnormality
abnormality
abnormality
abnormality
abnormality
abnormality
abnormality
abnormality
abnormality
Associated
Focal Sign
Left hemiparesis
Right hemiparesis
Right hemiparesis
Left hemiparesis
Outcome
Complete recovery within 1 day
Complete recovery within 1 day
Complete recovery within 1 day
Complete
Complete
Complete
Complete
Complete
Complete
Complete
Complete
Complete
Complete
recovery
recovery
recovery
recovery
recovery
recovery
recovery
recovery
recovery
recovery
within
within
within
within
within
within
within
within
within
within
1
1
1
1
1
1
1
1
1
1
day
day
day
day
day
day
day
day
day
day
Fig 2. Example of a hypoglycemic lesion in the internal capsule depicted by MR imaging (patient 4). DWI (A) reveals a hyperintensity lesion with decreased ADC (B ). No lesion is seen
in other MR imaging sequences such as FLAIR (C ) and T2-weighted (D) and T1-weighted (E) sequences. F, The DWI lesion disappeared completely next day.
(Fig 1A, -B). Additional focal lesions involving other highly
directional large white matter tract fibers were seen in 2 of
the 13 patients; one had a lesion in the cerebellar peduncle,
and the other, in the splenium of the corpus callosum in
addition to the internal capsule lesion (Table 1). These lesions were not detected in other MR imaging sequences (Fig
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Johkura 兩 AJNR 33 兩 May 2012 兩 www.ajnr.org
2A–E). In the remaining 10 patients, diffuse hyperintensity
lesions with decreased ADC involved the bilateral hemispheric white matter, including the corona radiata and centrum semiovale, in addition to the internal capsule
(Fig 1C, -D). The basal ganglia were also involved in 4 of the
10 patients in whom diffuse white matter lesions were iden-
Table 2: Clinical characteristics of comatose patients with hypoglycemic and diffuse DWI lesions
No./Age
(yr)/Sex
14/87/F
15/79/F
16/72/M
17/85/F
Blood Glucose
Levels (mg/dL)
45
25
64
40
18/61/M
55
19/83/F
20/85/M
21/93/F
22/91/F
23/74/F
35
23
10
17
36
a
DWI Lesion Distribution on Arrivala
Bilateral hemispheric white matter
Bilateral hemispheric white matter
Bilateral hemispheric white matter, bilateral basal ganglia
Bilateral hemispheric white matter, splenium of the corpus
callosum, bilateral basal ganglia, bilateral occipital
cortices
Bilateral hemispheric white matter, bilateral basal ganglia,
bilateral occipital cortices
Bilateral hemispheric white matter
Bilateral hemispheric white matter
Bilateral hemispheric white matter, left basal ganglia
Bilateral hemispheric white matter
Bilateral hemispheric white matter
DWI Lesions
the Next Day
No change
No change
No change
No change
1-Week Outcome
Died in 5 days
Vegetative
Vegetative
Vegetative
No change
Vegetative
No
No
No
No
No
Disoriented
Disoriented
Vegetative
Died in 4 days
Disoriented
change
change
change
change
change
Bilateral hemispheric white matter includes the bilateral internal capsules, bilateral corona radiata, and bilateral centrum semiovale.
tified on arrival; in 2 of the 4 patients with basal ganglia
lesions, the cerebral cortices were also involved (Table 2).
Initial DWI showed the absence of abnormal hyperintensity areas in 13 comatose patients with hypoglycemia. These 13
patients regained consciousness immediately after glucose infusion. The 13 patients with hyperintensity lesions involving
the internal capsule also regained consciousness within 1 day
after glucose infusion; they were without any neurologic deficit. It took several hours to recover in this group. Transient
hemiparesis was observed in 4 of these 13 patients before their
full recovery. The hyperintensity lesions disappeared completely by day 2 (Table 1 and Fig 2F). On the other hand, the 10
patients with diffuse white matter lesions did not regain consciousness by day 2 despite continuous adjustment of their
blood glucose levels: Two patients died, 5 patients remained in
a vegetative state, and 3 patients remained totally dependent
during the next week due to severe disorientation. The white
matter lesions did not disappear by day 2 or by 1 week after
admission. In fact, basal ganglia lesions became more conspicuous by day 2 in 1 of these patients (Fig 3). These lesions
became visible in other MR imaging sequences such as T2weighted and FLAIR sequences after day 2. The white matter
lesions became slightly less visible after 1 week (Fig 3).
Mean blood glucose levels of patients without hyperintensity lesions on arrival (mean age ⫽ 72.7 years), patients with
focal lesions involving the internal capsule (mean age ⫽ 76.2
years), and patients with diffuse white matter lesions (mean
age ⫽ 81.0 years) were 26.5, 29.8, and 35.0 mg/dL, respectively. There were no statistical differences in age or blood
glucose levels among the 3 groups.
Discussion
Neuroradiologically, our patients with hypoglycemia who
were in a comatose state on arrival comprised 3 groups: 1)
patients without hyperintensity lesions; 2) patients with focal
lesions involving highly directional large white matter tract
fibers of the internal capsule (and sometimes involving other
fibers of the cerebellar peduncle or splenium of the corpus
callosum); and 3) patients with diffuse lesions involving bilateral hemispheric white matter including the internal capsule,
corona radiata, and centrum semiovale (and sometimes the
basal ganglia or cerebral cortices). There are previous reports
of lesions involving not only white matter but also gray matter
in patients with hypoglycemic encephalopathy; selective involvement of gray matter has also been reported in such patients.11,12 In our study, however, most lesions were localized
in the white matter. This difference in the topographic lesion
pattern may arise from the severity of the disease and the time
of the MR imaging study. Hypoglycemic comatose patients
were included in our study regardless of the absence of MR
imaging abnormalities. MR imaging was performed prospectively in all patients upon arrival. However, previously reported subjects were included only when MR imaging studies,
performed within the first several days after admission, revealed areas of abnormal signaling.11,12 Thus, the previous reports might have included only the most serious cases of hypoglycemic encephalopathy, whereas we included patients at
various stages of hypoglycemic encephalopathy. In 1 of our
patients (patient 21), gray matter lesions were more conspicuous on day 2 images than on the initial images. Thus, it might
be possible that in some of the previously reported patients,
gray matter lesions had developed by the time MR imaging
studies were performed.
Our findings suggest that in comatose patients with hypoglycemia, the absence of hyperintensity lesions or the presence
of only focal lesions involving the internal capsule on initial
DWI predicts complete recovery within 1 day after glucose
administration. Indeed, immediate recovery after glucose infusion in patients with DWI-detected focal lesions involving
the internal capsule or other large white matter tract fibers has
been reported previously.4,7-10 Our findings also suggest that
diffuse lesions involving hemispheric white matter are a sign
of a poor 1-week outcome despite glucose administration.
Previously, both poor outcomes2-4,11 and good outcomes6,11
were reported for patients with diffuse white matter lesions on
initial DWI. However, when outcomes were good, it took several weeks for patients to recover completely.6,11 Although
1-week outcomes were poor for our 10 patients with diffuse
white matter lesions, gradual recovery might be expected during the next several weeks.
There was no significant difference in blood glucose levels
on admission between patients grouped according to the 3
imaging patterns. Lack of correlation between initial blood
glucose levels and prognosis has been reported.4,12 It might be
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907
Fig 3. Follow-up images of hemispheric white matter and basal ganglia lesions on DWI (A, B, E, F, I, J) and FLAIR (C, D, G, H, K, L) (patient 21). The white matter lesions on arrival (A⫺D) did
not disappear by day 2 (E⫺H) or by 1 week (I⫺L) after admission. The basal ganglia lesions became more conspicuous by day 2 (E⫺H) and became slightly less visible after 1 week (I⫺L).
that the duration of the hypoglycemic state, not the blood
glucose level, reflects the prognosis of patients with hypoglycemic encephalopathy. Evaluation of the relationship between
the duration of hypoglycemic state and the prognosis of patients will be needed in the future.
Glucose deprivation leads to severe energy failure and induces massive release of excitatory amino acids.13 Excessive
excitatory amino acid levels cause cytotoxic edema (ie, excitotoxic edema affecting neuronal and glial cells).14 Early brain
change in hypoglycemia is thought to comprise the excitotoxic
edema that propagates through neuron– glial cell units and
through transaxonal or trans-synaptic routes along the white
matter tracts.14,15 White matter lesions observed on MR images in our patients with hypoglycemic encephalopathy may
result from this excitotoxic edema. When excitotoxic edema,
detected by DWI focally involves large white matter tract fibers such as the internal capsule, irreversible hypoglycemic
neuronal damage may be minimal.14 However, when the excitotoxic edema spreads diffusely to the hemispheric white
matter, there is irreversible neuronal damage, mainly in the
cerebral cortices and basal ganglia, which are thought to be the
areas most vulnerable to glucose deprivation.1
Our study had several limitations. It was designed as a prospective study, but initial MR imaging evaluation was not
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Johkura 兩 AJNR 33 兩 May 2012 兩 www.ajnr.org
done by an observer blinded to clinical data. The possibility of
other concomitant brain damage such as hypoxic-ischemic
encephalopathy was not completely ruled out. Initial and outcome neurologic measurements of the patients were too simplified. Longer follow-up data, especially in patients with diffuse white matter lesions, may be needed.
Conclusions
To the best of our knowledge, ours is the first-reported prospective observational study of early MR imaging in comatose
patients with hypoglycemia. The white matter lesion pattern
depicted by DWI seems to have prognostic significance: No
lesions or only focal lesions involving the internal capsule on
initial DWI suggest complete recovery within 1 day after glucose administration, whereas diffuse lesions involving hemispheric white matter seem to be a sign of a poor 1-week outcome despite glucose administration.
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